Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy
da Silva, Priscila (Goethe-University Frankfurt)
Mora, Javier (University of Costa Rica)
You, Xin (Goethe-University Frankfurt)
Wiechmann, Svenja (Fraunhofer Institute for Translational Medicine and Pharmacology (Frankfurt, Alemanya))
Putyrski, Mateusz (Fraunhofer Institute for Translational Medicine and Pharmacology (Frankfurt, Alemanya))
Garcia-Pardo, Javier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Kannt, Aimo (Goethe-University Frankfurt)
Ernst, Andreas (Goethe-University Frankfurt)
Bruene, Bernhard (Goethe-University Frankfurt)
Weigert, Andreas (Goethe-University Frankfurt)

Date:	2024
Abstract:	The interleukin (IL)-1-family receptor antagonist IL-38 has emerged as a negative regulator of auto-inflammation. Given the intricate interplay between antitumor immunity and auto-inflammation, we hypothesized that blocking IL-38 may enhance tumor immune control. Our hypothesis was tested in the transgenic polyoma virus middle T oncoprotein mammary carcinoma model that is suitable for identifying strong immunomodulators. To investigate the effect of acute IL-38 blockade, we used a neutralizing antibody, alone or in combination with chemotherapy. Immune cell composition and location in tumors were determined by flow cytometry and immunohistochemistry, respectively. The role of γδ T cells was studied using an antibody blocking γδ T-cell receptor signaling. Whole transcriptome RNA sequencing and RNA expression analysis were employed to determine mechanisms downstream of IL-38 neutralization. Additionally, in vitro assays with γδ T cells, CD8+ T cells and cDC1, followed by in vivo CD8+ T cell depletion, were performed to study the underlying mechanistic pathways. Both, genetic ablation of IL-38 and neutralization with the antibody, reduced tumorigenesis, and IL-38 blockade improved chemotherapy efficacy. This was accompanied by an augmented lymphocyte infiltrate dominated by γδ T cells and CD8+ T cells, and signaling through the γδ-T-cell receptor was required for CD8+ T cell infiltration. Rather than directly interacting with CD8+ T cells, γδ T cells recruited conventional dendritic cells (cDC1) into tumors via the chemokine Xcl1. cDC1 in turn activated CD8+ T cells via the Notch pathway. Moreover, IL-38 negatively correlated with cDC1, XCL1-producing γδ T cells, T-cell infiltrates and survival in patients with mammary carcinoma. These data suggest that interfering with IL-38 improves antitumor immunity even in immunologically cold tumors.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Breast Cancer ; T cell ; Chemotherapy ; Antibody
Published in:	Journal for immunotherapy of cancer, Vol. 12 (august 2024) , ISSN 2051-1426

DOI: 10.1136/jitc-2023-008641
PMID: 39209451

15 p, 10.2 MB

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